Inflammatory responses to infection or injury are initiated by the adherence of leukocytes to the vascular wall (McEver et al, 1997, J. Clin. Invest., 100 (3): 485-492). Selectin represents a family of glycoproteins which mediate the first leukocyte-endothelial cell and leukocyte-platelet interactions during inflammation. The selectin family, which consists of L-selectin, E-selectin, and P-selectin, comprises an NH2-terminal lectin domain, followed by an EGF-like domain, a series of consensus repeats, a transmembrane domain, and a short cytoplasmic tail. The lectin domains of selectins interact with specific glycoconjugate ligands in order to facilitate cell adhesion. L-selectin, expressed on most leukocytes, binds to ligands on some endothelial cells and other leukocytes. E-selectin, expressed on cytokine activated endothelial cells, binds to ligands on most leukocytes. P-selectin, expressed on activated platelets and endothelial cells, also binds to ligands on most leukocytes.
P-selectin glycoprotein ligand-1 (“PSGL-1”), also known as SELPLG or CD162 (cluster of differentiation 162) is a human mucin-type glycoprotein ligand for all three selectins (Constantin, Gabriela, 2004, Drug News Perspect., 17(9): 579-585; McEver et al., 1997, J. Clin. Invest., 100 (3): 485-492). PSGL-1 is a disulfide-bonded homodimer with two 120-kD subunits and is expressed on the surface of monocytes, lymphocytes, granulocytes, and in some CD34+ stem cells. PSGL-1 is likely to contribute to pathological leukocyte recruitment in many inflammatory disorders since it facilitates the adhesive interactions of selectins. In addition, PSGL-1 is shown to have a unique regulatory role in T cells. Mice deficient in PSGL-1 show enhanced proliferative responses and autoimmunity, suggesting that PSGL-1 plays an important role in down-regulating T cell responses (Krystle M. et al. J. Immunol. 2012; 188:1638-1646. Urzainqui et al. Ann Rheum Dis 2013; 71:650; Pérez-Frías A, et al. Arthritis Rheumatol. 2014 November; 66(11):3178-89.; Angiari et al. J Immunol. 2013; 191(11):5489-500).
Several anti-PSGL-1 antibodies have been developed (see, e.g., International Application Pub. Nos. WO 2005/110475, WO 2003/013603, and WO 2012/174001; Constantin, Gabriela, 2004, Drug News Perspect., 17(9): 579-585, Chen et al. Blood. 2004; 104(10):3233-42, Huang et al, Eur J Immunol. 2005; 35(7):2239-49; and U.S. Pat. No. 7,604,800). Some of the existing agonistic PSGL-1 antibodies preferentially induce apoptosis of late-stage activated T cells but not other PSGL-1-expressing cells; such antibodies may therefore be useful as anti-inflammatory therapeutics, or for use in transplantations and/or transfusions. However, a need exists for improved anti-PSGL-1 antibodies with greater in vivo efficacy than existing antibodies.
All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.